Substituted saturated and unsaturated indole quinoline and benzazepine carboxamides and their use as pharmacological agents

ABSTRACT

This invention relates to a series of bicyclic benzomonoazacyclic carboxamide compounds of the general formula: ##STR1## Where Z is tertiary amine, which are useful for the method of treating patients suffering from gastrointestinal disorders, and of pharmaceutical composition including an effective 5HT3 - antagonists amount of said compounds therein.

This is a divisional of co-pending application Ser. No. 07/277,582 filedon Nov. 29, 1988 now U.S. Pat. No. 4,920,219.

FIELD OF THE INVENTION

This invention relates to azabicyclic substituted carboxamide compoundswhich exhibit 5-HT₃ antagonist properties including CNS, anti-emetic andgastric prokinetic activity which are void of any significant D₂receptor binding affinity. This invention also relates to pharmaceuticalcompositions and methods for the treatment of gastrointestinal andmental disorders using said compounds. This invention describes alsonovel processes for their preparation.

5-Hydroxytryptamine, abbreviated "5HT", is commonly known as serotonin.Serotonin is found throughout the body including the gastrointestinaltract, platelets, spleen and brain, and appears to be involved in agreat number of physiological processes such as a neurotransmitter atcertain neurones in the brain, and is implicated in a number of centralnervous system (CNS) disorders. Additionally, serotonin appears to actas a local hormone in the periphery: it is released in thegastrointestinal tract, where it increases small intestinal motility,inhibits stomach and colon motility, and stimulates stomach acidproduction. Serotonin is most likely involved in normal intestinalperistalsis.

The various physiological activities exerted by serotonin are related tothe variety of different receptors found on the surface membrane ofcells in different body tissue. The first classification of serotoninreceptors included two pharmacologically distinct receptors discoveredin the guinea pig ileum. The "D" receptor mediates smooth musclecontraction and the "M" receptor involves the depolarization ofcholinergic nerves and release of acetylcholine. Three different groupsof serotonin receptors have been identified and the following assignmentof receptors has been proposed: D-receptors are 5HT₂ -receptors;M-receptors are termed 5HT₃ -receptors; and all other receptors, whichare clearly not 5HT₂ or 5HT₃, should be referred to as 5HT₁ -like.

5HT₃ -receptors have been located in non-neurological tissue, braintissue, and a number of peripheral tissues related to differentresponses. It has been reported that 5HT₃ -receptors are located onperipheral neurones where they are related to serotonin's (excitatory)depolarizing action. The following subtypes of 5HT₃ receptor activityhave been reported: 5HT_(3B) subtype involving postganglionicsympathetic and parasympathetic neurones, leading to depolarization andrelease of noradrenaline and acetylcholine, respectively; 5HT_(3C)subtype involving on enteric neurones, where serotonin may modulate thelevel of acetylcholine; and 5HT_(3A) subtype involving on sensory nervessuch as those involved in the stimulation of heart nerve endings toproduce a reflex bradycardia, and also in the perception of pain.

Highly selective 5HT₃ -antagonists have been shown to be very effectiveat controlling and preventing emesis (vomiting) induced by chemotherapyand radiotherapy in cancer patients. The anti-emetic effects of 5HT₃-antagonists in animals exposed to cancer chemotherapy or radiation aresimilar to those seen following abdominal vagotomy. The antagonistcompounds are believed to act by blocking 5HT₃ -receptors situated onthe cell membranes of the tissue forming the vagal afferent input to theemetic coordinating areas on the brain stem.

Serotonin is also believed to be involved in the disorder known asmigraine headache. Serotonin released locally within the blood vesselsof the head is believed to interact with elements of the perivascularneural plexus of which the afferent, substance P-containing fibers ofthe trigeminal system are believed relevant to the condition. Byactivating specific sites on sensory neuronal terminals, serotonin isbelieved to generate pain directly and also indirectly by enhancing thenociceptive effects of other inflammatory mediators, for examplebradykinin. A further consequence of stimulating the afferent neuroneswould be the local release of substance P and possibly other sensorymediators, either directly or through an axon reflex mechanism, thanproviding a further contribution to the vascular changes and pain ofmigraine. Serotonin is known to cause pain when applied to the exposedblister base or after an intradermal injection; and it also greatlyenhances the pain response to bradykinin. In both cases, the painmessage is believed to involve specific 5HT₃ receptors on the primaryafferent neurones.

5HT₃ -antagonists are also reported to exert potential antipsychoticeffects, and are believed to be involved in anxiety. Although notunderstood well, the effect is believed to be related to the indirectblocking of serotonin 5HT₃ -mediated modulation of dopamine activity.

Many workers are investigating various compounds having 5HT₃ -antagonistactivity.

Reported Developments

The development of 5-HT₃ agents originated from work carried out withmetoclopramide (Beecham's Maxolon, A. H. Robins' Reglan), which ismarketed for use in the treatment of nausea and vomiting at high doses.Metoclopramide is a dopamine antagonist with weak 5HT₃ -antagonistactivity, which becomes more prominent at higher doses. It is reportedthat the 5HT₃ activity and not the dopamine antagonism is primarilyresponsible for its anti-emetic properties. Other workers areinvestigating this compound in connection with the pain and vomitingaccompanying migraine.

Merrell Dow's compound MDL-72222 is reported to be effective as an acutetherapy for migraine, but toxicity problems have reportedly ended workon this compound. Currently four compounds A. H. Robins' Zacopride,Beecham's BRL-43694, Glaxo's GR-38032F and Sandoz' ICS-205-930 are inclinical trials for use in chemotherapy-induced nausea and vomiting.GR-38032F is also in clinical trials for the treatment of anxiety andschizophrenia. Zacopride is reported to be in clinical trials foranxiety, while ICS205-930 is reported useful in the treatment ofcarcinoid syndrome.

Compounds reported as gastroprokinetic agents include Beecham'sBRL-24924, which is a serotonin-active agent for use in gut motilitydisorders such as gastric paresis, reflux esophagitis, and is know tohave also 5HT₃ -antagonist activity.

Metoclopramide, Zacopride, Cisapride and BRL-24924 are characterized bya carboxamide moiety situated para to the amino group of2-chloro-4-methoxy aniline. BRL-43694, ICS-205930, GR-38032F andGR-65630 are characterized by a carbonyl group in either the 3-positionof indole or N-benzoate, while Zacopride, BRL-24924, BRL-43694,ICS-205930 have also bridged azabicyclic groups in the form of acarboxamide or carboxylic ester.

Dibenzofurancarboxamides and 2-carboxamide-substituted benzoxepines arereported to have 5HT₃ -antagonist and gastroprokinetic activity incopending application Ser. Nos. 152,112, 152,192, and 168,824, all ofwhich are assigned to the same assignee as the present application.

SUMMARY OF THE INVENTION

This invention relates to bicyclic benzomonoazacyclic carboxamidecompounds having 5-HT3 antagonist activity gastric prokinetic,anti-emetic activity and lack D₂ receptor binding activity, and totherapuetic compositions comprising said compounds. Preferred compoundsof this invention are described by general Formula I: ##STR2## wherein:X is hydrogen, alkyl, alkoxy, hydroxy, amino, mono- and di-alkylamino,halo, trifluoromethyl, nitro, sulfamyl, mono- and di-alkylsulfamyl,alkylsulfonyl, carboxy, carbalkoxy, carbamyl or mono- anddi-alkylcarbamyl;

R is hydrogen, alkyl, formyl or acyl;

R₁ and R₂ are independently hydrogen or alkyl;

vicinal R₂ groups may together may be --(CH₂)_(a) -- where a is 1 to 4,thus forming a 3 to 6 membered ring;

vicinal R₁ groups together may form a double bond; when n is 3 thenvicinal R and R₁ groups together may form a double bond;

n is 2 to 4;

Y is hydrogen, alkyl, alkenyl, aralkyl, ##STR3## b and d are 1 to 4; Zis --(CR₁ R₂)_(d) --NR₁ R₂, ##STR4## and pharmaceutically acceptablesalts thereof.

This invention relates also to pharmaceutical compositions including aneffective therapeutic amount of the aforementioned bicyclicbenzomonoazacyclic carboxamide compounds of Formula I and therapeuticmethods for the treatment of a patient suffering from gastrointestinaldisorders and/or psychochemical imbalances in the brain by administeringsaid pharmaceutical composition.

DETAILED DESCRIPTION

As employed above and throughout the disclosure, the following, unlessotherwise indicated, shall be understood:

The choice of a R₁ or R₂ substituent group for a particular position inthe compound of Formula I does not limited other R₁ or R₂ groups to thesame substituent.

"Alkyl" means a saturated aliphatic hydrocarbon which may be eitherstraight or branched-chained containing from about 1 to about 6 carbonatoms.

"Lower alkyl" means an alkyl group as above, having 1 to about 4 carbonatoms.

"Aralkyl" means an alkyl group substituted by an aryl radical where arylmeans a phenyl or phenyl substituted with one or more substituents whichmay be alkyl, alkoxy, amino, nitro, carboxy, carboalkoxy, cyano, alkylamino, halo, hydroxy, hydroxyalkyl, mercaptyl, alkyl mercaptyl,carboalkyl or carbamoyl. The preferred aralkyl groups are benzyl orphenethyl.

"Carbamyl" means a group of the formula ##STR5##

"Alkoxy" means an alkyl-oxy group in which "alkyl" is as previouslydescribed. Lower alkoxy groups are preferred. Exemplary groups includemethoxy, ethoxy, n-propoxy, i-propoxy and n-butoxy.

"Acyl" means an organic radical derived from an organic acid, acarboxylic acid, by the removal of its acid hydroxyl group. Preferredacyl groups are benzoyl and lower alkyl carboxylic acids groups such asacetyl and propionyl.

The chemical nomenclature for the Z groups defined above are presentedbelow. ##STR6##

Certain of the compounds of the present invention may exist in enolic ortautomeric forms, and all of these forms are considered to be includedwithin the scope of this invention.

The compounds of this invention may be useful in the form of the freebase, in the form of salts and as a hydrate. All forms are within thescope of the invention. Acid addition salts may be formed and are simplya more convenient form for use; and in practice, use of the salt forminherently amounts to use of the base form. The acids which can be usedto prepare the acid addition salts include preferably those whichproduce, when combined with the free base, pharmaceutically acceptablesalts, that is, salts whose anions are non-toxic to the animal organismin pharmaceutical doses of the salts, so that the beneficial cardiotonicproperties inherent in the free base are not vitiated by side effectsascribable to the anions. Although pharmaceutically acceptable salts ofsaid basic compound are preferred, all acid addition salts are useful assources of the free base form even if the particular salt per se isdesired only as an intermediate product as, for example, when the saltis formed only for purposes of purification and identification, or whenit is used as an intermediate in preparing a pharmaceutically acceptablesalt by ion exchange procedures. Pharmaceutically acceptable saltswithin the scope of the invention are those derived from the followingacids: mineral acids such as hydrochloric acid, sulfuric acid,phosphoric acid and sulfamic acid; and organic acids such as aceticacid, maleic acid, citric acid, lactic acid, tartaric acid, malonicacid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and thelike. The corresponding acid addition salts comprise the following:hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate, lactate,tartarate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate, cyclohexylsulfamate and quinate, respectively.

The acid addition salts of the compounds of this invention are preparedeither by dissolving the free base in aqueous or aqueous-alcoholsolution or other suitable solvents containing the appropriate acid andisolating the salt by evaporating the solution, or by reacting the freebase and acid in an organic solvent, in which case the salt separatesdirectly or can be obtained by concentration of the solution.

A preferred class of compounds is described by Formula I where:

X is hydrogen, hydroxy, amino, mono- and di-loweralkylamino, halo,trifluoromethyl, sulfamyl, mono- and di-loweralkylsulfamyl orloweralkylsulfonyl;

R is hydrogen or loweralkyl;

R₁ and R₂ are independently hydrogen or loweralkyl;

vicinal R₂ groups together may be, --(CH₂)_(a) -- where a is 1 to 4,thus forming a 3 to 6 member ring;

n is 2 to 4;

Y is loweralkyl,

--(CR₁ R₂)_(b) --SO-loweralkyl or

--(CR₁ R₂)_(b) --CO-loweralkyl;

b and d are 1 to 3; and

Z is --(CR₁ R₂)_(d) --NR₁ R₂, ##STR7## and pharmaceutically acceptablesalts thereof.

The more preferred compounds are those of Formulae II, III and IV:##STR8## where X is hydrogen or halo;

R is hydrogen, methyl or ethyl;

R₁ and R₂ are independently hydrogen, methyl or ethyl;

Y is methyl, ethyl, propyl, i-propyl, butyl, i-butyl, sec-butyl,t-butyl, pentyl, --(CR₁ R₂)_(b) --SO-loweralkyl of 1-3 carbon atoms,--(CR₁ R₂)_(b) --CO-loweralkyl of 1-3 carbon atoms;

b is 1 to 3; and

Z is ##STR9## and pharmaceutically acceptable salts thereof.

The most preferred compounds are those of Formulae II, III and IV where:

X is chloro or bromo;

R is hydrogen or methyl;

R₁ and R₂ are independently hydrogen, methyl or ethyl;

Y is methyl; and

Z is ##STR10##

The compounds of this invention may be prepared by the following generalprocedure: ##STR11##

Condensation of the carboxylic acid of a substituted (1H)indole,quinoline, (1H)-1-benzazepine or the dihydro or tetrahydro forms thereofof Formula V or their acid halides or esters with an amine of theformula H₂ N-Z results in the corresponding carboxamide.

In general this reaction may be carried out at decreased temperatures,such as 0° C. by adding ethyl chloroformate to a reaction mixture of theacid in chloroform in the presence of triethylamine. This is thenreacted with the amine of the formula H₂ N-Z to obtain the desiredproduct. Condensation may also be carried out in the presence of adehydrating catalyst such as a carbodiimide in a solvent at normaltemperatures.

The starting materials of Formula V, that is the carboxylic acids of thesubstituted saturated and unsaturated indoles, quinolines andbenzazepines and more specifically (1H)indole, (1H)-2,3-dihydroindole,quinoline, 1,2,3,4,-tetrahydroquinoline, (3H)-4,5-dihydro-1-benzazepine,(1H)-1-benzazepine and (1H)-2,3,4,5-tetrohydro-1-benzazepine are alsonovel. They may be prepared by the reaction Schemes I, II and III below.The preparation of the [6,7] bicyclic ring systems is shown in ReactionScheme III. ##STR12##

Esterification of a substituted 2-methoxy-4-aminobenzoic acid (1)followed by demethylation of the alcohol and ester using borontribromide in a nonpolar solvent results in the 4-aminosalicylic acid(3). Esterification to the salicylate (4) followed by treatment withallylbromide under basic conditions gives the allylalcohol (5). Theamine may then be protected by acetylation of this group in the usualmanner in a pyridine medium (6). Claisen rearrangement at hightemperature results in the alkyl 3-allyl-4-acetyl-aminosalicylate (7).the alcohol is then alkylated (8) and cyclized preferably by treatmentwith osmium tetroxide in a nonpolar medium in the presence of sodiumperiodate which results in the corresponding2-hydroxy-(1H)-2,3-dihydroindole (9). Dehydration with triflouroaceticacid results in the formation of the 1-acetylindole compound (10). Thismay then be hydrogenated in the usual manner to the1-acetyl-2,3-dihydroindole (11) which may then be treated with base todeacetylate the nitrogen and obtain the desired4-alkoxy-5-carboxy-(1H)-2,3-dihydroindole (12). The 1-acetylindole (10)may also be deacetylated to obtain 4-alkoxy-5-carboxy-(1H)indole (13).##STR13##

When the 2-alkoxy-3allyl-4-acetylamino benzoate (8) is treated withborane-tetrahydrofuran in THF-diglyme followed by treatment withtrimethylamine N-oxide dihydrate at raised temperatures the3-(3-hydroxypropyl)benzoate (14) results. The tosylate is then made inthe usual manner with tosylcholoride and triethylamine and isdeacetylated to form (15) which is ring closed at raised temperatures ina nonpolar medium such as toluene. The resulting1,2,3,4-tetrahydroquinoline (16) is next treated with 10% NaOH to formthe acid (17). Dehydration of the ester (16) preferably usingN-bromosuccinimide gives the 3,4-dihydroquinoline product (19).Alternatively, using dichlorodicyanoquinone (DDQ) at raised temperaturesresults in the quinoline product (20). The acids (20) and (21) areobtained by desterification with base as above. ##STR14##

Friedel-Crafts acylation of a 4-substituted anisole with succinicanhydride results in the 2-(3-carboxypropionyl)anisole compound (23).Clemmensen reduction of the ketogroup using zinc amalgan andhydrochloric acid gives the butyric acid (24). Ring closure in thepresence of phosphorous pentoxide in methane sulfonic acid results inthe tetralone (25). When the latter is treated with hydroxylamine theketooxime product results (26). Beckmann rearrangement with phosphoruspentoxide in methane sulfonic acid gives the ring enlargement to thebenzazepinone (27). Bromination of the latter with NBS gives7-bromobenzazepinone (28). Reduction of the ketofunction usingborane-THF complex provides the benzazepine (29). Conversion of thebromo group to a carboxy group maybe effected by treatment with n-butyllithium and tetramethylethylenediamine followed by reacting with carbondioxide resulting in the9-substituted-6-methoxy-(lH)-2,3,4,5-tetrahydro-1-benzazepine-9-carboxylicacid (30). Dehydration of the tetrahydrobenzazepine by irradiating inthe presence of N-bromosuccinimide gives the (lH)-1-benzazepine product(31) while milder treatment with N-bromosuccinimide at 0° C. in basicsolution gives (3H)- 4,5-dihydro-l-benzazepine (32).

When it is desired that Y be other than methyl, when n is 2 or 3, the Ygroup other than methyl may be added to the -allyl-4-aminosalicylate ofcompound (7) when the alcohol is converted to the ether by using thecorresponding sulfate in place of dimethylsulfate. ##STR15##

On the other hand when n is 4, thus forming the benzazepine ring system,it is preferable to start the synthesis with the desired Y grouppresent. Thus the starting material should be of the formula ##STR16##

Appropriately desired end products having various X substituents can beprepared by using suitable reactions in order to convert one group toanother. Thus, for example when X is chloro, bromo or iodo, this may bereacted with cuprous cyanide in quinoline at about 150° C. to producethose compounds where X is cyano. This in turn may be converted to theacids, esters or amides.

The halo group may also be reacted with triflouromethyliodide and copperpowder at about 150° C. in DMF to obtain those compounds where X is CF₃.Halo may also be reacted with cuprous methanesulfinate in quinoline at150° C. to obtain th methylsulfonyl substituent.

When X is nitro, selective hydrogenation results in the correspondingamine, which may be mono- or di-alkylated with loweralkyl halides orsulfates. The amino group may also be diazotized to the diazoniumflouride which is then thermally decomposed to the flourine derivativecompound. The amine may also be diazotized and heated in an aqueousmedium to form the alcohol or heated in an alcohol to form the alkoxycompound. Chlorosulfonation of the amine group may form thecorresponding sulfamyl or mono- and di-alkylsulfamyl groups.

Depending on the chemistry involved in the synthesis, these reactionsmay be carried out at any appropriate stage of the synthesis. Forexample, the synthesis of X starting from NO₂ may be done after the ringclosed molecule or even after the carboxamide is prepared.

The compounds of this invention may contain at least one asymmetriccarbon atom and may have two centers when R₁ is not the same as R₂. As aresult, the compounds of Formula I may be obtained either as racemicmixtures or as individual enantiomers. When two asymmetric centers arepresent the product may exist as a mixture of two diasteromers. Theproduct may be synthesized as a mixture of the isomers and then desiredisomer separated by conventional techniques such as chromatography orfractional crystallization from which each diasteromer may be resolved.On the other hand, synthesis may be carried out by known sterospecificprocesses using the desired form of the intermediate which would resultin obtaining the desired specificity.

It is convenient to carry out condensation of the intermediatecarboxylic acids mentioned above with the amines of the formula H₂ N-Zusing the sterospecific materials. Accordingly, the acid may be resolvedinto its stereoisomers prior to condensation with resolved amine.

The compounds of this invention may be prepared by the followingrepresentative examples.

EXAMPLE 1 The Preparation of(N-1-Azabicyclo[2.2.2]Oct-3-yl)-7-Chloro-4-Methoxy-2.3-Dihydroindole-5-Carboxamide

Step 1. Methyl 2-methoxy-4-amino-5-chlorobenzoate

HCl gas is bubbled through a suspension of2-methoxy-4-amino-5-chlorobenzoic acid (39 g) in methanol (600 ml) whilecooled in an ice bath for 20 minutes. The mixture is evaporatedaffording the desired product as a solid which is used in the next step.

Step 2. 4-Amino-5-chlorosalicylic acid

A 0.1 molar solution of boron tribromide in methylene chloride (600 ml)is added to a stirred suspension of methyl2-methoxy-4-amino-5-chlorobenzoate (37 g) in methylene chloride (500ml). After stirring for 20 hrs, the mixture is poured into ice water,and the precipitate remaining in the reaction container is washed in theice water mixture with a solution of 5.5N NaOH (600 mls). The aqueouslayer is separated and acidified to pH3. The resulting precipitate isfiltered, washed with water and dried affording4-amino-5-chlorosalicylic acid which is used directly in the next step.

Step 3. Methyl 4-amino-5-chlorosalicylate

4-Amino-5-chlorosalicylic acid (24 g) is added to a stirred solution ofthionyl chloride (30 ml) in methanol (300 ml) cooled to 0° C., and themixture is stirred under reflux for 18 hours. The reaction mixture isevaporated and the residue is recrystallized from EtOH-H₂ O to givemethyl 4-amino-5-chlorosalicylate which is used directly in the nextstep.

Step 4. Methyl 2-allyloxy-4-amino-5-chlorobenzoate

A mixture of methyl 4-amino-5-chlorosalicylate (5 g), allyl bromide(12.6 g), ground K2CO3 (30 g) and acetone (120 ml) is stirred at refluxfor 5 hours and cooled to 25° C. The mixture is partitioned betweenmethylene chloride and H₂ O, the organic layer is separated, dried(MgSo₄), filtered and evaporated. The residue is recrystallized fromhexanechloroform affording the desired product as a crystalline solid(M.P. 107°-109° C.).

Step 5. Methyl 2-allyloxy-4-acetylamino-5-chlorobenzoate

Acetyl chloride (6.5 g) is added dropwise to a stirring solution of theamine of step 4 above (5 g) in pyridine (80 ml) cooled in an ice bath.The reaction mixture is allowed to warm to RT with stirring for 45minutes. Water is added, the mixture again cooled in ice, andpartitioned between H₂ O and CH₂ Cl₂. The organic layer is separated andwashed successively with H₂ O, 10% HCl, aqueous saturated NaHCO₃, dried,filtered and evaporated affording a solid residue which isrecrystallized from Hexane-Ethyl acetate, M.P. 110°-112° C. NMR (90 MHz,DMSO-d₆) shows the correct compound.

Step 6. Methyl 3-allyl-2-hydroxy-4-acetylamino-5-chlorobenzoate

A solution of the allyl ether (5 g) N N-dimethylaniline (70 ml) isstirred under reflux for 51/2 hours and cooled slowly to 25° C. Thereaction mixture is diluted with hexane and chilled in an ice bath. Theresulting precipitate is filtered, washed with hexane and driedaffording the desired products as crystalline needles. M.P. 189°-190° C.

Step 7. Methyl 3-allyl-2-methoxy-4-acetylamino-5-chlorobenzoate

A mixture of the phenolic compound of step 6 above (4 g) and NaH (0.7 g)in DMF (50 ml) is stirred for 15 minutes. Dimethyl sulfate (2 g) isadded and the mixture is stirred for 16 hours. The mixture ispartitioned between CH₂ Cl₂ and H₂ O, and the organic layer is separatedand washed with H₂ O, dried (MgSO₄) and evaporated. The solid residue istwice recrystallized from MeOH-H₂ O and chromatographed on silica gelaffording the desired product which is used in the next step.

Step 8. 1-Acetyl-5-carbomethoxy-7-chloro-4-methoxyindole

A 2.5% solution of osmium tetroxide in butanol (0.25 ml) is added to astirred solution of the methoxy compound from step 7 above (1.5 g) in H₂O-dioxane (15 ml/45 ml) and stirred for 30 minutes. Sodium periodate(2.25 g) is added portionwise over one hour and the reaction mixturestirred for 31/2 hours. Cyclohexene (1 ml) is added, the mixture stirredfor one hour, diluted with H₂ O and extracted with CHCl₃. The organiclayer is separated, dried (MgSO₄) and evaporated affording a gum whichis dissolved in TFA and allowed to stand for 15 minutes. The acidsolution is diluted to 100 mls with CH₂ Cl₂ and washed with H₂ O,saturated NaHCO₃, dried (MgSO₄) and evaporated affording a solid whichis chromatographed on silica gel affording a colorless solid which isthe indole as confirmed by NMR (270 MHz, CDCl₂).

Step 9. 1-Acetyl-5-carbomethoxy-7-chloro-4-methoxy-1,2-dihydroindole

The mixture of the indole of step 8 above (0.9 g) and Pt-C (0.2 g),acetic acid and MeOH (100 ml) is stirred under H₂ at latm. pressure for48 hours. The catalyst is filtered (celite), the filtered material iswashed (MeOH) and the reaction mixture and methanol washings areevaporated. The residue is diluted with CH₂ Cl₂, washed with saturatedNaHCO₃, dried (MgSO₄) and evaporated affording a colorless,semicrystalline material which is determined to be the desired compoundby NMR. M.P. 107°-109° C.

Step 10. 1-Acetyl-5-carboxy-7-chloro-4-methoxy-1,2-dihydroindole

A mixture of the indole ester of step 9 above (0.8 g) and 10% aqueousNaOH/MeOH (20 ml/80 ml) is stirred under reflux for 2 hours. Thereaction mixture is concentrated and the aqueous residue is diluted withwater and extracted with CHCl₃. The organic layer is dried (MgSO₄) andevaporated affording an off-white solid which is determined to be thedesired compound by NMR.

Step 11.(N-1-azabicyclo[2.2.2]oct-3-yl)-7-chloro-4-methoxy-2,3-dihydroindole-5-carboxamide

Ethyl chloroformate (25 ml) is added to a stirred mixture of the acidcompound of step 10 above (0.7 g) in CHCl₃ -Et₃ N (25 ml/0.7 g) chilledto -20° C. and stirring is continued for one hour. Aminoquinuclidine(2.8 g) and a saturated aqueous K2CO3 solution (7 ml) are added to thereaction mixture. Stirring is continued for 2 hours while slowly warningto RT. The mixture is diluted with CHCl₃ and H₂ O, stirred for 5 minutesand the aqueous layer was separated. The organic layer is washed with H₂O, dried (MgSO₄) and evaporated affording a foamy solid which isconverted to the dihydrochloride salt by dissolving in HCl-MeOH andevaporating the solvent. The desired product in the form of thedihydrochloride salt is a hygroscopic material is determined to be thecorrect material by NMR. M.P. =151°-153° C. Elemental Analysis: Calc'dC: 49.95, H 5.92, N 10.28; Found C: 50.58, H 6.20, N 9.98.

EXAMPLE 2 The Preparation of(N-1-Azabicyclo[2.2.2]oct-3-yl)-8-Chloro-5-Methoxy-1,2,3,4-Tetrahydroquinoline-6-Carboxamide

Step 1. Methyl 2-allyloxy-4-amino-5-chlorobenzoate

A mixture of methyl 4-amino-5-chlorosalicylate (5 g), allyl bromide(12.6 g), ground K2CO3 (30 g) and acetone (120 ml) is stirred at refluxfor 5 hours and cooled to 25° C. The mixture is partitioned betweenmethylene chloride and H₂ O, the organic layer is separated, dried(MgSO₄), filtered and evaporated. The residue is recrystallized fromhexane-chloroform affording the desired product as a crystalline solid(M.P. 107°-109° C).

Step 2. Methyl 3-allyl-2-hydroxy-4-amino-5-chlorobenzoate

A solution of the methyl 2-allyloxy-4-amino-5-chlorobenzoate (3.5 g) NN-diethylaniline (50 ml) is stirred under reflux for 1.5 hours, cooled,diluted with methylene chloride and washed with 10% aqueous HCl, driedand evaporated affording the desired product as an oil.

Step 3. Methyl 3-allyl-2-methoxy-4-amino-5-chlorobenzoate

A mixture of potassium carbonate (19 g), methyl iodide (8 g) and thephenolic compound of step 2 above (3.4 g) in acetone (100 ml) is stirredunder reflux for about 6.4 hours. The mixture is partitioned between CH₂Cl₂ and H₂ O, and the organic layer is separated and washed with 10%aqueous HCl, dried (MgSO₄) and evaporated affording an oil whichchromatographed on silica gel affording the desired product which isused in the next step.

Step 4. Methyl 3-(3-hydroxypropyl)-2-methoxy-4-amino-5-chlorobenzoate

A mixture of a 1 M solution of BH₃ in THF(8 ml) and the compound of step3 above (2 g) in THF-diglyme (10 ml/16 ml) is stirred under N₂ for 30minutes at 20° C. Me₃ NO.2H₂ O (2.2 g) is added to the mixture andrefluxed in a preheated oil bath allowing the THF to evaporate, followedby refluxing the mixture for one hour. The mixture is cooled to 20° C.,partitioned between CHCl₃ and sat'd aqueous NaHCO₃, and stirred for 30minutes. The organic layer is separated, washed with H₂ O, dried(MgSO₄), evaporated and the residue is chromatographed on silica gelaffording the desired product as a solid which is determined to be thecorrect product by NMR.

Step 5. 6-Carbomethoxy-8-chloro-5-methoxy-1,2,3,4-tetrahydroquinoline

A mixture of the compound of step 4 above (1.4 g), triethylamine (1 ml)and TsCl (1.1 g) in CH₂ Cl₂ is stirred at 25° C. for three days. Themixture is washed with saturated aqueous NaHCO₃ and evaporated affordinga residue which is dissolved in toluene and refluxed for 21/2 hours. Thetoluene is evaporated and the residue is dissolved in CH₂ Cl₂ and washedwith saturated NaHCO₃ (25 mls). The organic layer is dried, evaporatedand the residue chromatographed on silica gel affording a gum whichcrystallizes from Hex-Et₂ O to give the desired product (M.P. 105°-108°C.).

Step 6. 6-Carboxy-8-chloro-5-methoxy-1,2,3,4-tetrahydroquinoline

A mixture of the Compound of step 5 above (1.1 g), 10% aqueous NaOH (20ml) and MeOH (40 ml) is stirred under reflux for 30 minutes. The MeOH isevaporated and the aqueous residue partitioned with CHCl₃. The mixtureis stirred vigorously, cooled to 0° C. and treated with 10% HCl (28mls). The aqueous layer is separated and the organic layer is dried andevaporated. The residue is crystallized from ether affording the desiredproduct, M.P. 129°-132° C.

Step 7.(N-1-azabicyclo[2.2.2]oct-3-yl)-8-chloro-5-ethoxy-1,2,3,4-tetrahydroquinoline-6-carboxamide

Ethyl chloroformate (25 ml) is added to a stirred mixture of the acidcompound of step 6 above (0.7 g) in CHCl₃ -Et₃ N (25 ml/0.8 g) chilledto -20° C. and stirring is continued for 20 min. Aminoquinuclidine (3.1g) and a saturated aqueous K2CO3 solution (6 ml) are added to thereaction mixture. Stirring is continued for 30 minutes while slowlywarning to RT. The mixture is diluted with CHCl₃ and H₂ O, stirred for 5minutes and the aqueous layer was separated. The organic layer is washedwith H₂ O, dried (MgSO₄) and evaporated affording a foamy solid which ischromatographed on silica and converted to the hygroscopic hydrochloridesalt of the desired product, M.P. 160° C. Elemental Analysis: Calc'd C55.96, H 6.52, N 10.88; Calc'd(as Hydrate) C 53.47, H 6.73, N 10.39;Found C 53.45, H 7.34, N 10.26. The dihydrochloride salt has the samemelting point and the following elemental analysis: Calc'd C 51.13, H6.20, N 9.94; Found C 51.41, H 6.92, N 10.15.

EXAMPLE 3 The Preparation of(N-1-Azabicyclo[2.2.2]oct-3-yl)-9-Chloro-6-Methoxy-2,3,4,5-Tetrahydrobenzo(1H)-1-Azenine-7-Carboxamide

Step 1. 2-1-Oxo-3-carboxypronyl)-4-chloroanisole

A mixture of 4-chloroanisole (20 g), succinic anhydride (16 g) and AlCl₃(42 g) in 1:1 tetrachloroethylene/nitro-benzene (200 ml) is stirred at-10°-0° C. for a week. The mixture is poured into a conc. HCl/crushedice bath and the solvent is distilled under vacuo at 40° C. Theresulting suspension is made basic with 10% aqueous NaHCO3. The solidsare filtered and the filtrate made acidic forming a precipitate which isfiltered, washed with water, taken up in ethanol and dried. The solutionis filtered and evaporated affording the desired product as a whitesolid, M.p. 113°-115° C.

Step 2. 2-(3-Carboxyropyl)-4-chloroanisole

The acid compound of step 1 above is added to a stirring mixture oftoluene (22 ml), conc HCl (41 ml), water (17 ml) and the recoveredproduct of mossy zinc (22.2 g) and mercuric chloride (2.2 g) stirred inan aqueous HCl solution for about 10 minutes. The mixture is stirredunder reflux for about 16 hours, diluted with water, extracted withethyl acetate and the organic layer is dried filtered and evaporated.The residue is taken up in 10% aqueous NaOH, and dimethyl sulfate (about25 ml) added to the mixture which is heated to 80° C. The mixture isstirred at a constant temperature for about 4 hours, cooled, acidifiedand the resulting precipitate is filtered dried and used in the nextstep.

Step 3. 8-Chloro-5-methoxy-1,2,3,4-tetrahydronaphthal-1-one

The acid compound of step 2 above (6 g) is added to a solution ofphosphorous pentoxide (6.5 g) in methane sulphonic acid (50 g) andstirred at 60°-70° C. for about 2 hours. The reaction mixture is pouredinto water, extracted with ethyl acetate and the organic extract iswashed with 10% aqueous NaHCO₃, dried filtered and evaporated affordingthe desired bicyclic product as an oil.

Step 4. 8-Chloro-5-methoxy-1,2,3,4-tetrahydronanhthal-1-oxime

A mixture of the keto compound of step 3 above (2.6 g), hydroxylaminehydrochloride (0.9 g), pyridine (6 ml) and ethanol (60 ml) is stirredunder reflux for about 3 hours. The mixture is poured into 5% aqueousHCl and extracted with ethyl acetate. The organic extract is washed withacid, sat'd NaCl, dried filtered and evaporated affording the desiredcrude product as an oil which is used in the next step.

Step 5. 9-Chloro-6-methoxy-2,3,4,5-tetrahydro-benzo(1H)-1-azepin-2-one

The oxime compound of step 4 above (6.7 g), phosphorous pentoxide (16 g)and methane sulfonic acid (160 g) are stirred at 90°-100° C. for aboutan hour. The mixture is poured into ice water, and the resultingprecipitate is filtered, the filtered solid washed with water and takenup in methylene chloride. The organic solution is washed with 10%NaHCO₃, dried, filtered, evaporated and chromatographed (silica gel)affording the desired product as a solid which is used in the next step.

Step 6.7-Bromo-9-chloro-6-methoxy-2,3,4,5-tetrahydro-benzo(1H)-1-azepin-2-one

N-Bromosuccinimide (0.1 g) in DMF (5 ml) is added dropwise to a solutionof the benzazepine compound of step 5 above (0.15 g) in DMF (1 ml) at 0°C. and the mixture is allowed to equilibrate to RT. The mixture ispoured into water, extracted with ether, the extract is washed with 5%aqueous NaOH, water, dried, filtered and evaporated affording thedesired product as an oil.

Step 7.7-Bromo-9-chloro-6-methoxy-2,3,4,5-tetrahydro-benzo(1H)-1-azepine

Borane-THF (0.8 ml of 1M solution) is added dropwise to a solution ofthe bromobenzazepine compound of step 6 above (0.17 g) in dry THF (0.3ml) at 0° C. under argon. The mixture is stirred at reflux for about anhour, cooled and conc. HCl (0.3 ml) added. The mixture is diluted withwater, a 10% NaOH solution is added and the mixture is extracted withether. The organic extract is washed with sat's NaCl solution, dried,filtered and evaporated affording the reduced compound as an oil.

Step 8.7-Carboxy-9-chloro-6-methoxy-2,3,4,5-tetrahydro-benzo(1H)-1-azepine

A solution of the compound of step 7 above (0.08 g) in hexane is addeddropwise to a stirring mixture of n-butyl lithium (0.24 ml of 2.5 M inhexane) and tetramethylethyldiamine (0.07 ml) at a temperature of 0° C.Carbon dioxide gas is bubbled through the reaction mixture for one hourat 0° C. and stirred at RT overnight. The mixture is diluted with water,conc. HCl added and extracted with ethyl acetate. The ethyl acetatesolution is extracted with 10% NaOH, the basic solution made acidic andback extracted with ethyl acetate. The back extracted ethyl acetatesolution is washed with brine, dried and evaporated affording thedesired product as an oil.

Step 9.(N-1-azabicyclo[2.2.2]oct-3-yl)-9-chloro-6-methoxy-2,3,4,5-tetrahydro-benzo(1H)-1-azepine-7-carboxamide

Ethyl chloroformate (2.5 ml) is added to a stirred mixture of the acidcompound of step 8 above (0.07 g) in CHCl₃ -Et₃ N (2.5 ml/0.1 g) chilledto -20° C. and stirring is continued for 20 min. Aminoquinuclidine (0.3g) and a saturated aqueous K2CO3 solution (1 ml) are added to thereaction mixture. Stirring is continued for 30 minutes while slowlywarning to RT. The mixture is diluted with CHCl₃ and H₂ O, stirred for 5minutes and the aqueous layer was separated. The organic layer is washedwith H₂ O, dried (MgSO₄) and evaporated affording a solid which ischromatographed on silica and converted to the hydrochloride salt of thedesired product.

The following compounds are prepared by procedures analogous to thosedescribed above.

(N-1-Azabicyclo[2.2.2]oct-3-yl)-7-chloro-2,3-dihydro-2,2-dimethyl-4-methoxyindole-5-carboxamidedihydrochloride,

M.P.=150° C., Elemental Analysis: Calc'd C 52.24, H 6.46, N 9.62;Calc'd(as Hydrate) C 50.17, H 6.65, N 9.24; Found C 50.66, H 6.59, N9.35.

[N-(N',N'-diethylaminoethyl)]-7-Chloro-4-methoxy-2,2-dimethylindole-5-carboxamide,M.P.=148°-150° C. Elemental Analysis: Calc'd C 61.09, H 7.97, N 11.88;Found C 60.78, H 7.73, N 11.63.

N-(1-Azabicyclo[3.3.l]oct-4-yl)-7-chloro-4-methoxy-2,3-dihydroindole-5-carboxamide.

N-(1-Azabicyclo[3.3.1]oct-4-yl)-8-chloro-5-methoxy-1,2,3,4-tetrahydroquindine-6-carboxamide.

N-[2-(diethylamine)ethyl]-8-chloro-5-methoxy-1,2,3,4-tetrahydroquinoline-6-carboxamide.

N-(1-Azabicyclo[2.2.2]oct-3-yl)-9-chloro-6-methoxy-2,3,4,5-tetrahydrobenzo(1H)-1-azepine-7-carboxamide.

N-(1-Azabicyclo[3.3.1]oct-4-yl)-9-chloro-6-methoxy-2,3,4,5-tetrahydrobenzo(1H)-1-azepine-7-carboxamide.

N-[2-(diethylamino)ethyl]-9-chloro-6-methoxy-2,3,4,5-tetrahydrobenzo(1H)-1-azepine-7-carboxamide.

We have found that the compounds of this invention have gastricprokinetic, anti-emetic activity and lack D₂ receptor binding activityand as such possess therapeutic value in the treatment of upper bowelmotility and gastroesophageal reflux disorders. Further, the compoundsof this invention may be useful in the treatment of disorders related toimpared gastrointestinal motility such as retarded gastric emptying,dyspepsia, flatulence, oesophageal reflux, peptic ulcer and emesis. Thecompounds of this invention exhibit 5-HT₃ antagonism and are consideredto be useful in the treatment of psychotic disorders such asschizophrenia and anxiety and in the prophylaxis treatment of migraineand cluster headaches. We have further found that these compounds areselective in that they have little or no dopaminergic antagonistactivity.

Various tests in animals can be carried out to show the ability of thecompounds of this invention to exhibit pharmacological responses thatcan be correlated with activity in humans. These tests involve suchfactors as the emesis, selective antagonism of 5-HT₃ receptors and theirD₂ dopamine receptor binding properties.

It has been found that the compounds of this invention when tested inthe above variety of situations show a marked activity.

One such test is the "Rat Gastric Emptying: Amberlite Bead Method". Thistest is carried out as follows:

The study is designed to assess the effects of a test agent on gastricemptying of a solid meal in the rat. The procedure is a modification ofthose used in L. E. Borella and W. Lippmann (1980) Diqestion 20: 26-49.

Procedure

Amberlite beads are placed in a phenol red solution and allowed to soakfor several hours. Phenol red serves as an indicator, changing the beadsfrom yellow to purple as their environment becomes more basic. Aftersoaking, the beads are rinsed with 0.1 NaOH to make them purple and thenwashed with deionized water to wash away the NaOH.

The beads are filtered several times through 1.18 and 1.4 mm sieves toobtain beads with diameters in between these sizes. This is done usinglarge quantities of deionized water. The beads are stored in salineuntil ready to use.

Male Sprague-Dawley rats are fasted 24 hours prior to the study withwater ad libitum. Rats are randomly divided in treatment groups with anN of 6 or 7.

Test agents are prepared in 0.5% methylcellulose and administered to therats orally in a 10 ml/kg dose volume. Control rats receive 0.5%methylcellulose, 10 ml/kg p.o. One hour after dosing, rats are given 60Amberlite beads intragastrically. The beads are delivered via a 3 inchpiece o pE 205 tubing attached to a 16 gauge tubing is placed inside thetubing adapter to prevent the beads from being pulled back into thesyringe. The beads are flushed into each rat's stomach with 1 ml saline.

Rats are sacrificed 30 minutes after receiving the beads and theirstomachs are removed. The number of beads remaining in each stomach iscounted after rinsing the beads with NaOH.

The number of beads remaining in each stomach is subtracted from 60 toobtain the number of beads emptied. The mean number of beads ± S.E.M. isdetermined for each treatment group. The percent change from control iscalculated as follows: ##EQU1##

In order to demonstrate the ability of the compounds of this inventionas anti-emetic agents the following test for "Cisplatin-Induced Emesisin the Ferret" may be used. This test is a modified version of a paperreported by A. P. Florezyk, J. E. Schurig and W. T. Brodner in CancerTreatment Reports: Vol. 66, No. 1. January 1982.

Cisplatin had been shown to cause emesis in the dog and cat. Florczyk,et al. have used the ferret to demonstrate the same effects.

Procedure

Male castrated, Fitch ferrets, weighing between 1.0 and 1.5 kg have anIndwelling catheter placed in the jugular vein. After a 2-3 day recoveryperiod, the experimental procedure is begun.

30 minutes prior to administration of Cisplatin, ferrets are dosed withthe compound in 0.9% saline (i.v.) at a dose volume of 2.0 ml/kg.

45 minutes after administration of Cisplatin, ferrets are again dosedwith 0.9% saline (i.v.) mixture at a dose volume of 2.0 ml/kg.

Cisplatin is administered (i.v.) 30 minutes after the first dosing withthe 0.9% saline. Cisplatin, 10 mg/kg is administered in a dose volume of2.0 ml/kg.

The time of Cisplatin administration is taken as time zero. Ferrets areobserved for the duration of the experiment (4 hours). The elapsed timeto the first emetic episode is noted and recorded, as are the totalnumber of periods of emesis.

An emetic (vomiting) episode is characterized by agitated behavior, suchas pacing around the cage and rapid to and fro movements. Concurrentwith this behavior are several retching movements in a row, followed bya single, large, retch which may or may not expulse gastric contents.Immediately following the single large retch, the ferret relaxes. Singlecoughs or retches are not counted as vomiting episodes.

D-2 Dopamine Receptor Binding Assay

The D-2 dopamine receptor binding assay has been developed with slightmodifications using the method of Ian Cresse, Robert Schneider andSolomon H. Snyder, Europ. J. Pharmacol. 46: 377-381(1977). Spiroperidolis a butyrophenone neuroleptic whose affinity for dopamine receptors inbrain tissue is greater than that of any other known drug. It is ahighly specific D-1 dopamine (non-cyclase linked) receptor agent with K₁values of 0.1-0.5 for D-2 inhibition and 300 nM for D-1 inhibition.

Sodium ions are important regulators of dopamine receptors. The affinityof the D-2 receptor is markedly enhanced by the presence of millimolarconcentrations of sodium chloride. The Kd in the absence and presence of120 mM sodium chloride is 1.2 and 0.086 nM respectively. Sodium chloride(120 mM) is included in all assays as a standard condition.

The caudate nucleum (corpus striatum) is used as the receptor sourcebecause it contained the highest density of dopamine receptors in thebrain and periphery.

Procedure

Male Charles-River rats weighing 250-300 g are decapitated and theirbrains removed, cooled on ice, and caudate dissected immediately andfrozen on dry ice. Tissue can be stored indefinitely at -70° C. Forassay caudate is homogenized in 30 ml of tris buffer (pH 7.7 at 25° C.)using the polytron homogenizer. The homogenate is centrifuged at 40,000g (18,000-19,000 RPM in SS-34 rotor) for 15 minutes. Pellet isresuspended in fresh buffer and centrifuged again. The final pellet isresuspended in 150 volumes of assay buffer.

Specific ³ H-spiroperidol binding is assayed in a total 2 ml reactionvolume consisting of 500 μl of caudate homogenate, 50 mM tris buffer (pH7.4 at 35° C.), 5 mM MgSO₄, 2 mM EDTA 2NA, 120 mM NaCl, 0.1% ascorbicacid, 0.4 nM ³ H-spiroperidol and test compound or assay buffer. Whencatecholamines are included in the assay, 10 μM pargyline should beincluded in the reaction mixture to inhibit monoamine oxidase. Samplesare incubated at 35° C. for 30 minutes followed by addition of 5 ml icecold 50 mM TRIS (pH 7.7 at 25° C.) and filtration through GF/B glassfiber filters on a Brandel Receptor Binding Filtration apparatus.Filters are washed twice with an additional 5 ml of tris buffer each.Assay groups are performed in triplicate and 1 μM D(+) butaclamol isused to determine nonspecific binding. Filters are placed in vialscontaining 10 ml of Ecoscint phosphor, shaken for 30 minutes and dpmdetermined by liquid scintillation spectrophotometry using a quenchcurve. Proteins are determined by the method of Bradford, M. Anal.Biochem 72, 248(1976) using Bio-Rad's coomassie blue G-250 dye reagent.Bovine gamma Globulin supplied by BIO-RAD is used as the proteinstandard.

Bezold-Jarisch effect in anesthetized rats

Male rats 260-290 g are anesthetized with urethane 1.25 g/kg⁻¹ i.p., andthe trachea cannulated. The jugular vein is cannulated for intravenous(i.v.) injection of drugs. Blood pressure is recorded from a cannula inthe left carotid artery and connected to a haparin/saline-filledpressure transducer. Continuous heart rate measurements are taken fromthe blood pressure recordings. The Bezold-Jarisch effect is evoked byrapid, bolus i.v. injections of 5-HT and measurements are made of thefall in heart rate. In each rate, consistent responses are firstestablished with the minimum dose of 5-HT that evokes a clear fall inheart rate. Injections of 5-HT are given every 12 minutes and adose-response curve for the test compound is established by injectingincreasing doses of compound 5 minutes before each injection of 5-HT.The effect of the compound on the 5-HT-evoked bradycardia is calculatedas a percent of the bradycardia evoked by 5-HT before injection ofcompound.

In separate experiments to measure the duration of 5-HT antagonismcaused by the compounds of this invention, a single dose of compound isinjected 5 minutes before 5-HT, and the effects of 7 repeated challengeswith 5-HT are then monitored. The effects of the compound on theefferent vagal limb of the Bezold-Jarisch reflex are checked byelectrically stimulating the peripheral end of a cut vagus nerve.Unipolar electrical stimulation is applied every 5 minutes via a pair ofsilver electrodes, using 1 ms rectangular pulses in 5 strains with amaximally-effective voltage (20 V at 10 Hz). Pulse frequency may varyfrom 5-30 Hz and frequency-response curves are constructed before and 10minutes after i.v. injection of a single dose of compound.

The results of these above tests indicate that the compounds for thisinvention exhibit a valuable balance between the peripheral and centralaction of the nervous system and may be useful in the treatment ofdisorders related to impaired gastro-intestinal motility such as gastricemptying, dyspepsia, flatulence, esophageal reflux and peptic ulcer andin the treatment of disorders of the central nervous system such aspsychosis.

The compounds of the present invention can be administered to amammalian host in a variety of forms adapted to the chosen route ofadministration, i.e., orally, or parenterally. Parenteral administrationin this respect includes administration by the following routes:intravenous, intramuscular, subcutaneous, intraocular, intrasynovial,transepthelially including transdermal, opthalmic, sublingual andbuccal; topically including opthalmic, dermal, ocular, rectal and nasalinhalation via insufflation and aerosol and rectal systemic.

The active compound may be orally administered, for example, with aninert diluent or with an assimilable edible carrier, or it may beenclosed in hard or soft shell gelatin capsules, or it may be compressedinto tablets, or it may be incorporated directly with the food of thediet. For oral therapeutic administration, the active compound may beincorporated with excipient and used in the form of ingestible tablets,buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers,and the like. Such compositions and preparations may, of course, bevaried and may conveniently be between about 2 to about 6% of the weightof the unit. The amount of active compound in such therapeuticallyuseful compositions is such that a suitable dosage will be obtained.Preferred compositions or preparations according to the presentinvention are prepared so that an oral dosage unit form contains betweenabout 50 and 300 mg of active compound.

The tablets, troches, pills, capsules and the like may also contain thefollowing: A binder such as gum tragacanth, acacia, corn starch orgelating; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose of saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier. Various other materials may be present ascoatings or to otherwise modify the physical form of the dosage unit.For instance, tablets, pills, or capsules may be coated with shellac,sugar or both. A syrup or elixir may contain the active compound sucroseas a sweetening agent, methyl and propylparabens as preservatives, a dyeand flavoring such as cherry or orange flavor. Of course, any materialused in preparing any dosage unit form should be pharmaceutically pureand substantially non-toxic in the amounts employed. In addition, theactive compound may be incorporated into sustained-release preparationsand formulations.

The active compound may also be administered parenterally orintraperiotoneally. Solutions of the active compound as a free base orpharmacologically acceptable salt can be prepared in water suitablymixed with a surfactant such as hydroxypropylcellulose. Dispersion canalso be prepared in glycerol, liquid polyethylene glycols, and mixturesthereof and in oils. Under ordinary conditions of storage and use, thesepreparations contain a preservative to prevent the growth ofmicroorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases the form must be sterile and must be fluid tothe extent that easy syringability exists. It may be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, andliquid polyethylene glycol, and the like), suitable mixtures thereof,and vegetable oils. The proper fluidity can be maintained, for example,by the use of a coating such as lecithin, by the maintenance of therequired particle size in the case of dispersion and by the use ofsurfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimersal, andthe like. In many cases, it will be preferable to include isotonicagents, for example, sugars or sodium chloride. Prolonged absorption ofthe injectable compositions of agent delaying absorption, for example,aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredient into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum drying and the freeze dryingtechnique which yield a powder of the active ingredient plus anyadditional desired ingredient from previously sterile-filtered solutionthereof.

The therapeutic compounds of this invention may be administered to amammal alone or in combination with pharmaceutically acceptablecarriers, as noted above, the proportion of which is determined by thesolubility and chemical nature of the compound, chosen route ofadministration and standard pharmaceutical practice.

The physician will determine the dosage of the present therapeuticagents which will be most suitable for prophylaxis or treatment and willvary with the form of administration and the particular compound chosen,and also, it will vary with the particular patient under treatment. Hewill generally wish to initiate treatment with small dosages by smallincrements until the optimum effect under the circumstances is reached.The therapeutic dosage will generally be from 0.1 to 20 mg or from about0.01 mg to about 5 mg/kg of body weight per day and higher although itmay be administered in several different dosage units from once toseveral times a day. Higher dosages are required for oraladministration.

We claim:
 1. A method for the treatment of a patient suffering fromgastrointestinal disorders comprising administering thereto agastrointestinal effective amount of a compound according to the formula##STR17## wherein X is hydrogen, hydroxy, amino, mono- anddi-loweralkylamino, halo, trifluoromethyl, sulfamyl, mono- anddi-loweralkylsulfamyl or loweralkylsulfonyl;R is hydrogen or loweralkyl;R₁ and R₂ are independently hydrogen or loweralkyl; vicinal R₂ groupstogether may be --(CH₂)_(a) -- where a is 1 to 4, thus forming a 3 to 6member ring; n is 2 to 4; Y is loweralkyl, --(CR₁ R₂)_(b)--SO-loweralkyl or --(CR₁ R₂)_(b) --CO-loweralkyl; b and d are 1 to 3;and Z is --(CR₁ R₂)_(d) --NR₁ R₂, ##STR18## or a pharmaceuticallyacceptable salt thereof.
 2. A pharmaceutical composition including aneffective 5-HT₃ -antagonist amount of a compound according to theformula ##STR19## wherein X is hydrogen, hydroxy, amino, mono- anddi-loweralkylamino, halo, trifluoromethyl, sulfamyl, mono- anddi-loweralkylsulfamyl or loweralkylsulfonyl;R is hydrogen or loweralkyl;R₁ and R₂ are independently hydrogen or loweralkyl; vicinal R₂ groupstogether may be --(CH₂)_(a) -- where a is 1 to 4, thus forming a 3 to 6member ring; n is 2 to 4; Y is loweralkyl, --(CR₁ R₂)_(b)--SO-loweralkyl or --(CR₁ R₂)_(b) --CO-loweralkyl; b and d are 1 to 3;and Z is --(CR₁ R₂)_(d) --NR₁ R₂, ##STR20## or a pharmaceuticallyacceptable salt thereof in admixture with a pharmaceutical carrier.